The present invention relates to quinazoline compounds, compositions and therapeutic methods for the treatment of cancers by administering quinazoline compounds.
Currently, there is a need for methods useful for preventing the development or recurrence of cancer in mammals. Quinazoline compounds have been suggested as useful compounds in the treatment of cell growth and differentiation characterized by activity of the human epidermal growth factor receptor type2 (HER2). See, for example, Myers et.al., U.S. Pat. No. 5,721,237. Some quinazoline derivatives have been suggested as useful as anti-cancer agents for the treatment of specific receptor tyrosine kinase-expressing cancers, especially those expressing epithelial growth factor (EGF) receptor tyrosine kinase. See, for example, Barker et. al., U.S. Pat. No. 5,457,105. It is generally taught that quinazolines exert their anti-tumor effects via tyrosine kinase inhibition. However, while some quinazoline compounds inhibit the growth of tumor cells, such as brain tumor cells, others with equally potent tyrosine kinase inhibitory activity fail to do so (Naria et.al., 1998, Clin. Cancer Res. 4:1405-1414; Naria et.al., 1998, Clin. Cancer Res. 4:2463-2471).
Some quinazoline derivatives have also been suggested as useful agents for treating precancerous legions and inhibiting the growth of neoplastic cells. See for example, Pamukeu et al., U.S. Pat. Nos. 5,990,117; 6,037,345; and 6,046,206. Although many of the disclosed quinazoline derivatives are useful for treating precancerous legions and inhibiting the growth of neoplastic cells, there still exists the need to discover better compounds for the treatment of cancer, in particular colorectal cancer.
Cancer of the colon and/or rectum is now the third most common cause of death from cancer in the United States. Over 150,000 new cases of colon and/or rectal cancer are diagnosed each year. In addition, the incidence of colon cancer reportedly increases with age, particularly after the age of 40. Since the mean ages of populations in America and Western Europe are increasing, the prevalence of colorectal cancer should increase in the future.
To date, the only effective cure for colorectal cancer is surgery at an extremely early stage. Unfortunately, most cases of colorectal cancer are discovered too late for surgical cure. In many cases, the patient does not experience symptoms until the cancer has progressed to a malignant stage. The search for drugs useful for treating and preventing colorectal cancer continues.
What is needed in the art is a useful therapeutic agent for the treatment of colorectal cancer.
It has been discovered that 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline is effective as a therapeutic agent for the treatment of colorectal cancer. The present invention demonstrates the improved chemopreventive activity of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline compared to known therapeutic agents.
The present invention provides a method of preventing the development or recurrence of colorectal cancer in a mammal comprising administering to the mammal, an effective cancer preventative amount of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, or a pharmaceutically acceptable salt thereof.
The present invention also provides the use of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, or a pharmaceutically acceptable salt thereof, to prepare a medicament useful for preventing the development or recurrence of colorectal cancer in a mammal.
These and other features and advantages of the present invention will become apparent after a review of the following detailed description of the disclosed embodiments and the appended claims.
It has been discovered unexpectedly that 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline possesses increased activity against colorectal cancer. As such, 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline is particularly useful as an active agent for anticancer compositions and for methods of treating cancers, such as colorectal cancer.
A number of terms are used throughout the present disclosure. Some of these terms are defined as shown below.
All scientific and technical terms used in this application have meanings commonly used in the art unless otherwise specified. As used in this application, the following words or phrases have the meanings specified.
As used herein, xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d means any material which, when combined with 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, allows 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline to retain biological activity, such as the ability to potentiate antibacterial activity of mast cells and macrophages. Examples include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsions, and various types of wetting agents. Compositions comprising such carriers are formulated by well-known conventional methods (see, for example, Remington""s Pharmaceutical Sciences, Chapter 43, 14th Ed., Mack Publishing Co., Easton, Pa.).
The term xe2x80x9cconjugatexe2x80x9d means a compound formed as a composite between two or more molecules. More specifically, in the present invention, 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline is bonded, for example, covalently bonded, to cell-specific targeting moieties forming a conjugate compound for efficient and specific delivery of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline to a cell of interest.
The phrase xe2x80x9ctargeting moietyxe2x80x9d means a molecule, which serves to deliver 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline to a specific site for the desired activity. Targeting moieties include, for example, molecules that specifically bind molecules on a specific cell surface. Such targeting moieties useful in the present invention include anti-cell surface antigen antibodies. Cytokines, including interleukins and factors such as granulocyte/macrophage stimulating factor (GMCSF) are also specific targeting moieties, known to bind to specific cells expressing high levels of their receptors.
The term xe2x80x9cprodrug moietyxe2x80x9d is a substitution group, which facilitates use of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, for example by facilitating entry of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline into cells or administration of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline. The prodrug moiety may be cleaved from 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, for example by cleavage enzymes in vivo. Examples of prodrug moieties include phosphate groups, peptide linkers, and sugars, which moieties can be hydrolyzed in vivo.
As used herein, xe2x80x9cinhibitxe2x80x9d means to reduce by a measurable amount, or to prevent entirely.
As used herein, xe2x80x9cto treatxe2x80x9d means to inhibit or block at least one symptom that characterizes a pathologic condition, in a mammal threatened by, or afflicted with, the condition.
Compounds for use in the present invention include 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, or pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may include organic acid addition salts formed with acids, which form a physiological acceptable anion, including, but not limited to, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, and a-glycerophosphate. Suitable inorganic salts may also be formed, including, but not limited to, hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
Acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline useful in the present invention may be synthesized from a key starting material, 4-chloro-6,7-dimethoxyquinazoline, prepared using published procedures (Nomoto, et al., 1990, Chem. Pharm. Bull., 38:1591-1595; Thomas, C. L., 1970, Academic Press, New York, N.Y., xe2x80x9cI. Synthesis of quinazoline derivativesxe2x80x9d) as outlined below in Scheme 1 and as described more fully in the Examples below: 
4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline is then prepared by the condensation of 4-chloro-6,7-dimethoxyquinazoline with 4-aminophenol as outlined below in Scheme 2: 
4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be useful as a pharmaceutical composition prepared with a therapeutically effective amount of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline and a pharmaceutically acceptable carrier or diluent.
4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be formulated as a pharmaceutical composition and administered to a mammalian host, such as a human patient, in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
Thus, 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier, or by inhalation or insufflation. The components may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient""s diet. For oral therapeutic administration, 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be combined with a fine inert powdered carrier and inhaled by the subject or insufflated. Such compositions and preparations preferably contain at least 0.1 wt % of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline. The percentage of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline within a composition or preparation may, of course, be varied and may conveniently be between about 2 to about 60 wt % of a given unit dosage form. The amount of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline in such therapeutically useful compositions is such that an effective dosage level will be obtained.
The tablets, troches, pills, capsules, and the like may also contain one or more of the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
In addition, 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be incorporated into sustained-release preparations and devices. Further, 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be administered intravenously or intraperitoneally by infusion or injection. Solutions of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders comprising 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle may be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity may be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms may be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions may be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions may be prepared by incorporating 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying techniques, which yield a powder of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline plus any additional desired ingredient present in the previously sterile-filtered solutions.
Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Other solid carriers include nontoxic polymeric nanoparticles or microparticles. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
Generally, the concentration of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline in a liquid composition will be from about 0.1 to about 25 wt %, preferably from about 0.5 to about 10 wt %. The concentration of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline in a semi-solid or solid composition such as a gel or a powder will be about 0.1 to about 5 wt %, preferably about 0.5 to about 2.5 wt %.
The amount of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline required for use in a given treatment will vary depending on a number of factors including, but not limited to, the route of administration, the nature of the condition being treated, and the age and condition of the patient. The amount of a given dosage will be ultimately at the discretion of the attendant physician or clinician. In general, however, a suitable dose will be in the range of from about 0.1 mg/kg to about 100 mg/kg of body weight per day. Preferably, the dose will range from about 10 to about 75 mg/kg of body weight per day, more preferably from about 3 to about 50 mg/kg of body weight per day, even more preferably from about 6 to about 90 mg/kg of body weight per day, and even more preferably from about 15 to 60 mg/kg of body weight per day.
4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline is conveniently administered in unit dosage form; for example, containing from about 5 to about 1000 mg, preferably from about 10 to about 750 mg, and more preferably from about 50 to about 500 mg of active ingredient per unit dosage form.
Ideally, 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline is administered to achieve peak plasma concentrations of from about 0.5 to about 75 xcexcM, preferably from about 1 to about 50 xcexcM, and more preferably from about 2 to about 30 xcexcM. This may be achieved, for example, by the intravenous injection of a 0.05 to 5 wt % solution of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, optionally in saline, or orally administered as a bolus containing about 1 to 100 mg of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline. Desirable blood levels may be maintained by continuous infusion to provide about 0.01 to about 5.0 mg/kg/hr or by intermittent infusions containing from about 0.4 to about 15 mg/kg of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline.
4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations, such as multiple inhalations from an insufflator.
In one aspect of the present invention, 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be targeted to cells where treatment is desired, in particular, to colorectal cells. 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may be targeted to the desired cell by conjugation to a targeting moiety that specifically binds to the desired cell, thereby directing administration of a conjugated molecule. Useful targeting moieties are ligands, which specifically bind cell antigens or cell surface ligands, for example, antibodies against the B cell antigen, CD19 (such as B43) and the like.
To form conjugates for use in the present invention, targeting moieties are covalently bonded to sites on 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline. The targeting moiety, which is often a polypeptide molecule, is bound to 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline at reactive sites, including, but not limited to, OH, and the like. Specific linking agents are used to join the compounds. Preferred linking agents are chosen according to the reactive site to which the targeting moiety is to be attached.
Methods for selecting an appropriate linking agent and reactive site for attachment of the targeting moiety to 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline are known, and are described, for example, in Hermanson, et al., Bioconjugate Techniques, Academic Press, 1996; Hennanson, et al., Immobilized Affinity Ligand Techniques, Academic Press, 1992; and Pierce Catalog and Handbook, 1996, pp. T155-T201.
The ability of 4-(4xe2x80x2-hydroxyphenyl)amino-6,7-dimethoxyquinazoline to prevent the development or recurrence of a cancer may be determined using pharmacological models, which are well known to the art, or using the methods as described herein. As used herein, preventing the development or recurrence includes both slowing the development or recurrence, as well as completely eliminating the development or recurrence.